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MyDermatology-Bolognia > Wolverton-Anti-TNFs, IL-12/23, IL-23s and IL-17s > Flashcards

Wolverton-Anti-TNFs, IL-12/23, IL-23s and IL-17s Flashcards

1
Q

What are the two TNF receptors? Which has higher affinity for TNF-alpha?

A

P55 and P75

P55 5-fold higher affinity for TNF-alpha (but high dissociation rate)

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2
Q

What is the source of Etanercept? Adalimumab? Infliximab?

A

Etanercept: fully human
Adalimumab: fully human
Infliximab: Chimeric human-mouse

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3
Q

What is etanercept?

A

Etanercept is a dimeric fusion protein of p75 TNF receptor linked to Fc IgG 1

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4
Q

What does etanercept bind to

A

Binds to both TNF-α and TNF-β; binding to soluble and membrane bound TNF-α

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5
Q

What is adalimumab and its components

A

Fully human monoclonal antibody of IgG1

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6
Q

What does adalimumab bind to

A

TNF-α only

inhibits TNF binding to p55 and p75 transmembrane TNF receptor

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7
Q

What is infliximab and its components

A

Chimeric (25% mouse, 75% human) monoclonal antibody of IgG1 kappa

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8
Q

What does infliximab bind to?

A

TNF-α only, inhibits binding to soluble and transmembrane TNF receptor

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9
Q

What is certolizumab and its components

A

Recombinant human Fab’ antibody conjugated with polyethylene glycol

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10
Q

What does certolizumab bind to?

A

TNF-α only

binding to soluble and transmembrane bound TNF-α

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11
Q

What is the half life of etanercept

A

5 days

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12
Q

What is the standard dosing regimen for Etanercept for psoriasis?

A

50 mg twice weekly for 3 months then 50 mg weekly

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13
Q

What is the trade name for etanercept

A

Enbrel

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14
Q

What is the half life of infliximab?

A

7-days at 5mg/kg

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15
Q

What is the standard dosing regimen for inflixmab for psoriasis?

A

3–5 mg/kg per injection; typically given at baseline, 2 weeks, 6 weeks, then every 8 weeks thereafter

E.g. 210-350 for 70 kg person

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16
Q

What is the half life of adalimumab?

A

14 days

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17
Q

What is the dosing for adalimimab for psoriasis? for HS?

A

80 mg loading dose at baseline, 40 mg at 1 week, then 40 mg every 2 weeks thereafter

For HS-160, then 80 at week 2, then 40 at week 4 then 40 weekly after

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18
Q

What is the dosing for certolizumab

A

400 mg every 2 weeks;

200 mg every 2 weeks can be considered for patients <90 kg in weight (after initial loading dose)

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19
Q

What is the half life of certolizumab

A

14 days

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20
Q

List 5 conditions etanercept is FDA approved for? Name 2 TNF-treated conditions that it is NOT approved for

A

Etanercept:
1. RA
2. Psoriasis
3. PsA
4. JIA
5. Ank spond

NOT approved for IBD
RCT showed no efficacy for HS

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21
Q

List 4 dermatological conditions etanercept is used off-label to treat?

A
  1. Severe drug reactions-SJS/TEN
  2. Granulomatous dermatoses-sarcoid, generalized GA
  3. Vasculitis-PAN, GCA, takayasauas
  4. Neutrophilic dermatoses-behcets, PG
  5. PRP
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22
Q

What is the PASI75 efficacy for etanercept

A

50%

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23
Q

What ages is etanercept approved for?

A

2-17 and then adults

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24
Q

Name 8 contraindications for Anti-TNF therapy

A
  1. Active malignancy
  2. Active uncontrolled infection-e.g. active hep B>C, TB
  3. Hypersensitivity
  4. concurrent anakitnra medications

Relative
5. MS or another demyelinating d/o or strong fam hx
6. CHD-NYHA class III and above
7. Pregnant/breast feeding

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25
Q

What is the pregnancy category of Etanercept

A

B

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26
Q

Name 6 serious AE of TNF inhibitors to discuss with patients

A
  1. Increased risk lymphoma-debated, but probably there
  2. Increased risk NMSC
  3. Increased risk infections-e.g. fungal, TB reactivation in latent TB, Hep B reactivation in chronic carriers, sepsis
  4. Demyelinating d/o like MS, optic neuritis, or GBS (rare, case reports), no official link
  5. Worsening of CHF
  6. Autoimmunity-ANA/anti dsDNA induction, sometimes SLE
  7. Hematologic toxicity-rare
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27
Q

What is the paediatric dose of etanercept

A

0.8 mg/kg per week in divided doses

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28
Q

What is infliximab approved for

A

IBD
RA
Ank spond
JIA
PsO
PsA

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29
Q

What is the PASI75 efficacy for infliximab

A

80%

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30
Q

What is the rate of ADAs in etanercept, infliximab and adalimumab?

A

Etanercept- rare
Inflixmab 10% in RA patients, 38% in psoriasis
ADA-5%

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31
Q

Name 5 off label uses for infliximab

A
  1. HS
  2. Neutrophilic-PG, Behcets
  3. Vasculitis-systemic, refractory KD
  4. Granulomatous dermatoses
  5. PRP
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31
Q

Name 5 off label uses for infliximab

A
  1. HS
  2. Neutrophilic-PG, Behcets
  3. Vasculitis-systemic, refractory KD
  4. Granulomatous dermatoses
  5. PRP
32
Q

What does of infliximab was harmful for patients with NYHA Class III or higher CHF?

A

> 5 mg/kg (10 mg/kg group)
Thus probably fine for psoriasis

33
Q

Name 4 ways to try and combat ADA in inflixmab

A
  1. premedication with oral corticosteroids
  2. continuing with maintenance dosing after induction,
  3. increasing the dose per kilogram
  4. shortening the interval between doses
  5. Concomitant immunosuppressant
33
Q

What is an adverse event more related to infliximab

A

Hepatotoxicity, AI hepatitis, and/or choletstasis that can be fatal and w/out LE elevations

34
Q

What is adalimumab FDA approved for? List 6

A

RA
juvenile idiopathic arthritis
psoriatic arthritis
ankylosing spondylitis
Crohn disease (adult and pediatric)
ulcerative colitis
plaque psoriasis
HS
uveitis.

35
Q

What is adalimumab FDA approved for? List 6

A

RA
Juvenile idiopathic arthritis
Psoriatic arthritis
Ankylosing spondylitis
Crohn disease (adult and pediatric)
ulcerative colitis
Plaque psoriasis
HS
Uveitis

36
Q

What is one major difference between PIONEER I vs. II

A

One major difference between the two trials was that patients were required to stop oral antibiotics in PIONEER I, whereas they were allowed to continue oral antibiotic treatment in PIONEER II.

37
Q

What % of patients with mod-sever HS achieve HISCR (50% reduction)

A

41.8% to 58.9%

38
Q

What is different about certolizumab from other anti TNFs? What are 2 clinical implications of this?

A

It does not contain an Fc portion (only Fab) thus it does not fix complement, does not cause complement dependent cytotoxicity, and should not cause antibody-dependent cell-mediated cytotoxicity.

Also placental transfer is Fc-receptor mediated, thus unable to cross placenta

39
Q

What is the purpose of PEG on certolizumab

A

Extends half life by 14 days

40
Q

Name the FDA indications for certolizumab

A

Chrons
IBD
RA
Ank spond
PsO and PsA

41
Q

What were the PASI-75 rates for certolizumab 400 mg q 2weeks at 12 weeks

42
Q

What is ustekinumab and what does it bind to

A

fully human monoclonal immunoglobulin G (IgG)1κ antibody that binds to the shared p40 subunit of IL-12 and IL-23

43
Q

What is the core MOA of IL-12/23s

A

Prevents the interaction of IL-12 and 23 with IL-12Rβ1 and inhibiting the activity of both interleukins on T-cell differentiation and cytokine production

44
Q

What is the half life of ustekinumab

45
Q

What is the dosing for ustekinumab for psoriasis

A
  • Weight (kg) ≤100 kg: 45 mg subcutaneously initially and 4 weeks later, then every 12 weeks
  • Weight (kg) >100 kg: 90 mg subcutaneously initially and 4 weeks later, then every 12 weeks
46
Q

What age groups is Stelara approved for in psoriasis

47
Q

What are the two subunits of IL-23

48
Q

What does IL-12 do in psoriasis pathogenesis

A

IL-12 induces differentiation of naïve T cells into Th1 cells that produce TNF-α, IFN-γ, and IL-2.

49
Q

What does IL-23 do in psoriasis pathogenesis

A

IL-23 induces differentiation of naïve T cells to Th17 cells

50
Q

What cells produce IL-12 and 23

A

Activate dendritic cells

51
Q

Which cytokines are produced by TH17 cells

A

IL-17A
IL-17F
IL-22
TNF-α

52
Q

Which cytokines drive keratinocyte proliferation seen in psoriasis

A

IL-17A and IL-17F primarily drive keratinocyte proliferation that is observed in psoriasis

53
Q

What is the efficacy of ustekinumab in terms of PASI75

54
Q

What is the PASI-90 of secukinumab vs. ustekinumab? What was the name of the trial

A

PASI 90 was roughly 80% vs. 60% at week 16, secukinumab better thus in the CLEAR trial

55
Q

What is the PASI-100 of brodalumab vs. ustekinumab? What was the name of the trial

A

PASI-100 was achieved at week 12 in 40% of patients on brodalumab vs. 20% of patients on ustekinumab.

AMAGINE 2 and AMAGINE 3 trials

56
Q

With ustekinumab, when is response seen and when is peak response?

A

Clinical responses were apparent by 2 weeks, with maximal response rates seen after about 6 months.

57
Q

Name 3 benefits of ustekinumab including the multiple things it is approved for

A

q3 month dosing

Peds/adolescent patients

Also approved for IBD, PsA (6+)

58
Q

What is Stelara NOT approved for

A

HS
RA
ANK spend

59
Q

What are the 2 most common AE in Stelara

A

Nasopharyngitis and headache

60
Q

Is there a significantly increase risk of MACE with biologics

A

No stat sig
But sl. increases

61
Q

What subunit of IL-23 do IL-23 inhibitors target?

62
Q

What are the 3 IL-23 inhibitors and their dosing schedules

A

Guselkumab-Tremfya

Tildrakizumab-Illumya

Rizankizumab- Skyrizi

63
Q

What is the dosing for Skyrizi?

A

150 mg at weeks 0, 4, then every 12 weeks

64
Q

What is the dosing for tremfya

A

100 mg at week 0, 4, then every 8 weeks

65
Q

What is the dosing illumya

A

100 mg at 0, 4 12 weeks

66
Q

Which IL-23 inhibitor is approved for PsA

A

Guselkumab/tremfya

67
Q

What is the half life for guselkumab, skyrizia and tildrakizumab

A

Guselkumab: 15-18
Tildra: 23 days
Rizan: 20-28

68
Q

What is the PASI-75 for guselkumab

69
Q

What is the main cytokine secreted by TH17 cells?

70
Q

Name the 3 currently approved IL-17s, biologic and trade name

A

Secukinumab-Cosentyx
Brodalumab-Siliq
Ixekizumab-Taltz

71
Q

What is the dosing for cosentyx? Siliq? Taltz?

A

Cosentyx: 300 mg SC weeks 0, 1, 2, 3, 4, then q4w

Siliq: 210 mg SC weeks 0, 1, 2, and then q2w

Taltz: 160 mg SC at week 0 –> 80 mg at weeks 2, 4, 6, 8, 10, 12, then 80 mg q4w (q2weeks x 3 months then monthly)

72
Q

What is the average PASI-75 for cosentyx

73
Q

What is cosentyx approved for

74
Q

What are 3 off label uses for cosentyx

A

HS
Palmoplantar psoriasis
Generalized pustular psoriasis

75
Q

What is one thing to warn patient using cosentyx that doesn’t apply to the other 17s

A

Latex coated cap, so careful with latex allergy

76
Q

What is one thing to warn patient using cosentyx that doesn’t apply to the other 17s

A

Latex coated cap, so careful with latex allergy

MyDermatology-Bolognia (31 decks)

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